Manipulating the immune system Flashcards
Immunotherapy
Treatment to stimulate or restore the ability of the immune system to fight infection and disease
Uses of antibodies in manipulation
Direct admin of antibodies to treat diseases
Using antibodies to direct toxins, drugs, or cells to target tumours
Uses of T cells in manipulation
Enhance normal responses (vaccination strategy)
Adding lab-grown T cell back into patients (adoptive transfer)
Antibodies are suitable treatment for:
Immune or inflammatory diseases
Infections and cancer
Antibodies have potential to be good drugs for what 4 reasons?
High specificity
Well-characterised structure and biochemistry
Normal body components
Made against anything
How do antibodies work as drugs?
Mostly by neutralising a molecule that’s important in disease progress
4 types of drug antibodies based on how similar they are to human antibodies
Fully mouse (-omab)
Chimeric (-ximab)
Humanised (-zumab)
Fully human (-umab)
Adalimub
Fully human antibody
Anti-TNFalpha therapy for inflammation of joints and skin, eg RA
Limitations of antibodies as drugs
Cost
Treatment but not a cure
Global availability
Three ways for antibodies to target tumour cells
Tumour-specific antibody
Tumour-specific antibody (or antibody fragment) conjugated to toxin
Tumour-specific antibody (or antibody fragment) conjugated to radionuclide
Tumour-specific antibody
Binds to tumour cells; NK cells are activated to kill tumour cells
Tumour-specific antibody (or antibody fragment) conjugated to toxin
Binds to tumour cells; conjugates are internalised, killing the cell
Tumour-specific antibody (or antibody fragment) conjugated to radionuclide
Radioactive antibody binds to tumour cell; radiation kills tumour cell & neighbouring tumour cells
How do we know tumours are immunogenic?
Mouse models -
irradiated tumour & leaves proteins behind, proteins are introduced to mouse, mouse had immune response
Challenge mouse with cells from same tumour -> recognised and defended against by immune response
Challenge mouse with cells from different tumour -> not eliminated, no pre-existing immunity
Evidence for immune response to tumours in humans
Specific cytotoxic and proliferative immune responses in vitro
Increased incidence of cancer in immunosuppressed patients
Why does the immune system not prevent cancer from developing?
Tumours mya be recognised early on but a variant tumour can arise that is more resistant to being killed
Over time more and more variants develop
Eventually one variant escapes the killing mechanism or recruits regulatory cells to protect it and therefore spreads unchallenged
T cell therapy 2 basic approaches
1) Vaccines to induce T cell response to tumour antigens
2) Immunisation by isolating T cells from patients, expanding in the lab and putting them back into patients (adoptive transfer)
3 challenges of t cell therapy
Vaccination may not be sufficient to activate correct or enough t cells
Being able to isolate specific t cells - may not be possible to expand on enough to put back into the patient
HLA matching - donor T cells w recipient
Engineered T cells for tumour immunotherapy
1) isolate genes for TCR from tumour-specific t cell clone, then transduce into polyclonal t cells - enables sufficient t cells to be grown w correct antigen/HLA specificity
2) Grow large numbers of t cells with specificity for tumour cell defined by a Chimeric Antigen Receptor
CAR t cell therapy
develop a t cell w a CAR protein on the cell surface
CAR protein is made up of antibody variable domain joined to cytoplasmic tail that contains a t cell co-stimulatory domain and a signalling domain
